Abstract P4-08-12: Clinical and Genomic Landscape of Breast Cancers Carrying CCNE1 Amplification
Authors: Antonio Marra, Pier Selenica, Yingjie Zhu, Pedram Razavi, Anton Safonov, Emanuela Ferraro, Sarat Chandarlapaty, Jorge Reis-Filho
Journal: Cancer Research (2023)

Abstract Background: Cyclin E1 (CCNE1) plays a critical role in cell cycle regulation. CCNE1 overexpression and/or gene amplification (amp) have been associated with poor outcome in several tumors, including breast cancer (BC). CCNE1 amp has recently been identified as a potential therapeutic target for novel synthetic lethality-based therapies. Here we sought to define the clinical and genomic features of BCs carrying CCNE1 amp. Methods: Genomic and clinical data from all consecutive BCs, which had been subjected to targeted sequencing using the FDA-authorized MSK-IMPACT assay from April 2014 to December 2021, were retrieved. Allele-specific copy number and fraction genome altered (FGA) were assessed using FACETS. Whole genome doubling (WGD) status was inferred from MSK-IMPACT sequencing data. Samples were categorized as CCNE1 amp or non-amp based on copy number profile assessed by FACETS. Mutual exclusivity and co-occurrence analyses between CCNE1 amp and other genetic alterations were performed using CoMEt. Multiple testing correction using the Benjamini–Hochberg procedure was applied to control for the false discovery rate. Progression-free survival (PFS) was assessed by Kaplan Meier method and Cox proportional-hazards models. Survival analyses were restricted to only patients with available pre-treatment samples. Results: Of 3,753 BCs with full clinical and genomic data, 125 (3.3%) harbored CCNE1 amp. A significant difference in the proportion of CCNE1 amp between treatment-naïve and post-treatment/metastatic samples was observed (2.4% vs 4%, p=0.007). CCNE1 amp was significantly less frequently detected in hormone receptor (HR)+/HER2- BCs than in HR-/HER2+ and HR-/HER2- subtypes (2% vs 7.6% and 7.2%, respectively, p&amp;lt; 0.001), and was particularly rare in invasive lobular BCs (1/452 cases). BCs with CCNE1 amp displayed a higher frequency of WGD (p&amp;lt; 0.001) and higher median FGA (p&amp;lt; 0.001) than non-amp tumors, overall and in different subtypes, suggesting increased genomic instability. No difference in tumor mutational burden (TMB) between CCNE1 amp and non-amp was found. In primary BC (n=1,385), a higher proportion of TP53 alterations was found in cases with CCNE1 amp (odds ratio [OR] 6.0, 95% confidence interval [CI] 2.5-16.6, q&amp;lt; 0.001). Conversely, CCNE1 amp was mutually exclusive with CDH1 alterations (q&amp;lt; 0.001). Comparable results were found in the analysis of post-treatment/metastatic samples (n=2,368). A subset analysis on HR+/HER2- BCs confirmed that TP53 (OR 4.2, 95%CI 2.28-8.11, q&amp;lt; 0.001) and CDH1 (OR 0.09, 95%CI 0.002-0.57, q&amp;lt; 0.1) alterations co-occurred and were mutually exclusive, respectively, with CCNE1 amp. ARID2 alterations were also enriched in HR+/HER2- tumors harboring CCNE1 amp (OR 10.6, 95%CI 2.54-33.93, q&amp;lt; 0.1). CCNE1 amp was significantly associated with reduced median PFS (8.8 vs 15.2 months in CCNE1 amp [n=9] vs CCNE1 non-amp [n=402]; hazard ratio [HR] 2.82, 95% CI 1.38-5.75, p=0.004) on first line treatment with CDK4/6 inhibitor plus endocrine therapy (ET) in HR+/HER2- metastatic BCs, regardless of the ET partner, FGA and TMB. CCNE1 amp was also associated with numerically inferior median PFS (7.3 vs 20.8 months in CCNE1 amp [n=5] vs CCNE1 non-amp [n=106]; HR 3.1, 95% CI 1.24-7.87, p=0.01) on first line trastuzumab/pertuzumab/taxane treatment in HER2+ metastatic BCs, with a trend toward significance after adjusting for FGA and TMB (p=0.09). Conclusions: CCNE1 amp is associated with specific clinicopathological and genomic features in BCs and linked to an increased genomic instability. CCNE1 amp defines a subset of metastatic BCs with marked poor clinical response to available standard-of-care treatments. Further studies testing novel therapeutic approaches, including synthetic lethality-based strategies targeting CCNE1 amp and CDK2-selective inhibition, are warranted. Citation Format: Antonio Marra, Pier Selenica, Yingjie Zhu, Pedram Razavi, Anton Safonov, Emanuela Ferraro, Sarat Chandarlapaty, Jorge Reis-Filho. Clinical and Genomic Landscape of Breast Cancers Carrying CCNE1 Amplification [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-12.